The objectives of this program project include the following: 1) To complete studies designed to test the hypothesis that persistent infection with hepatitis B virus (HBV) is required for the development of most cases of primary hepatocellular carcinoma (PHC). Substantial data supporting this view have been collected, but additional effort is required to complete the studies. 2) To learn more of the natural history of HBV infection in human populations, including its effect on mortality, fertility, and sex ratio; studies of transmission within families and by insect vectors (bedbugs); interactions with nutritional factors (iron, protein-calorie malnutrition) and other biological materials. These studies will increase our basic knowledge of this unusual infectious agent and help in the design of public health strategies for the prevention of infection with HBV. This includes the use of the vaccine against HBV, developed in our laboratory during the earlier years of this grant. 3) To identify other viruses similar to HBV (termed "Icrons") which are also related to common cancers or other diseases. Two (and possibly a third) virus-cancer relations of this kind have been identified in lower animals, two of them at The Institute for Cancer Research. To this end, we are developing a "type specimen" description of HBV, the first of the Icrons, and other viruses now known to be similar to it (i.e. woodchuck hepatitis virus, WHV). 4) To investigate a novel cellular model for the pathogenesis of PHC. The experiments are designed to evaluate the roles of hepatocytes which are susceptible or resistant to infection with HBV in the development of chronic liver disease and clinical liver cancer.